To investigate the effect of low-dose rhythmic transdermal 17-β-estradiol on serum P1NP (marker of bone formation) and CTX (marker for bone resorption), versus continuous low-dose and standard-dose continuous transdermal 17-β-…
ID
Source
Brief title
Condition
- Other condition
- Bone disorders (excl congenital and fractures)
Synonym
Health condition
preventie osteoporose
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The endpoint is the interaction between treatment and time on serum P1NP
levels. (Does the change over time differ between the treatment arms?). The
primary outcome will be measured every two weeks from baseline until 16 weeks
of treatment.
Secondary outcome
1. The secondary endpoint is the interaction between treatment and time on
serum CTX levels. (Does the change over time differ between the treatment
arms?) The outcome will be measured every two weeks from baseline until 16
weeks of treatment.
2. Mean change of fasting glucose, fasting insulin, 2-hour post OGTT glucose
and insulin and liver steatosis (CAP score) after 16 weeks of treatment. These
parameters will be measured at baseline and after 16 weeks.
3. Sleep quality (PSQI) and chronotype (MCTQ) and menopausal symptoms (GCS)
after 16 weeks in relation to baseline.
4. In a subgroup: To assess the effect of low-dose rhythmic transdermal 17-β-
estradiol versus continuous low-dose and standard-dose continuous transdermal
17-β-estradiol on 17-β-estradiol transcriptional regulation in adipose tissue
using ChipSeq and RNA seq analysis (hypothesis-generating).
Background summary
Postmenopausal estrogen deficiency leads to accelerated bone resorption,
resulting in an increased risk of osteoporosis and osteoporotic fractures.
Continuous estrogen replacement therapy (ERT) with 17-β-estradiol is an
effective treatment for the prevention of osteoporosis in postmenopausal women.
ERT normalizes bone turnover by attenuating bone remodelling, reflected by a
decrease of bone turnover markers procollagen type 1 N propeptide (P1NP) and
C-terminal telopeptide of type 1 collagen (CTX). Notably, estrogen replacement
can also induce an anabolic effect in bone tissue, which is not well studied.
The anabolic effect of 17-β-estradiol occurs when continuous estrogen
replacement therapy is first initiated. After initiation of 17-β-estradiol
therapy, serum concentrations of bone formation marker P1NP rise, while a
decrease of bone resorption marker CTX is observed, suggesting that an increase
of serum 17-β-estradiol generates an initial anabolic response in bone tissue.
Similarly, when serum 17-β-estradiol levels physiologically increase during the
luteal phase of the menstrual cycle, a simultaneous increase of P1NP is
observed, in combination with a decrease of CTX levels. Therefore, we
hypothesize that, by mimicking the rhythmic estrogen concentrations during the
menstrual cycle in postmenopausal women, a subsequent rhythmic rise of bone
formation marker P1NP can be induced, and as a result, improved bone formation.
In addition to the regulation of bone metabolism, estrogens regulate
key features of glucose metabolism and energy expenditure. Estrogen deficiency
after menopause leads to accumulation of visceral fat, as well as altered
insulin sensitivity and insulin secretion. A previous meta-analysis
demonstrated that estrogen replacement therapy (ERT) has beneficial effects on
insulin resistance and fasting glucose levels in postmenopausal women. Oral HRT
produced larger beneficial effects glucose than transdermal HRT. However,
transdermal estrogen was administered continuously in all studies. We
hypothesize that rhythmic transdermal estrogen administration may produce
larger beneficial effects on glucose regulation than continuous transdermal
estrogen administration, in postmenopausal women.
The increase in visceral fat that is observed in estrogen deficiency is
partly the result of classical (genomic) estrogen effects on adipose tissue.
Estrogen therapy in postmenopausal women decreases the expression of genes
involved in lipogenesis (including LPL and FAS). However, it is unknown how
rhytmic 17-β-estradiol will affect this gene expression on a transcriptional
level. We will perform ChipSeq and RNA Seq analysis of the effect of rhythmic
17-β-estradiol versus low-dose and standard-dose continuous 17-β-estradiol on
transcriptional regulation in subcutaneous adipose tissue.
Study objective
To investigate the effect of low-dose rhythmic transdermal 17-β-estradiol on
serum P1NP (marker of bone formation) and CTX (marker for bone resorption),
versus continuous low-dose and standard-dose continuous transdermal 17-β-
estradiol administration.
This study will aid to improve understanding of estrogen-mediated effects on
bone turnover in postmenopausal women. Furthermore, this study will lead to
advancements of knowledge to improve the estrogen treatment regimen for
prevention of osteoporosis in postmenopausal women.
Study design
We will conduct a monocenter open-label randomized controlled trial,
investigating the effect of rhythmic 17-β-estradiol versus low-dose and
standard-dose continuous 17-β-estradiol on bone turnover markers P1NP and CTX.
This monocenter study will be set at Amsterdam UMC, location AMC and the study
duration is 16 weeks.
Intervention
Each treatment arm has a treatment duration of 16 weeks (4 cycles of 4 weeks).
A transdermal treatment regimen will be implemented. The risk venous
thromboembolism is not elevated in transdermal estrogen users when compared to
non-users of estrogen. The risk of breast cancer and ovarian cancer is not
increased when estrogen replacement therapy is used for less than 1 year.
Recent prospective studies suggest that transdermal estrogen therapy (<=50ug/
24hrs) does not elevate stroke risk.
• Group 1. Rhythmic 17-β-estradiol:
Alternating cycles consisting of transdermal 17-β-estradiol 25 µg/24 hr for two
weeks,
followed by two weeks of transdermal 17-β-estradiol 50 µg /24 hr. Estrogen
therapy will be
combined with continuous oral micronized progesterone 100 mg once daily in the
evening.
• Group 2. Low-dose continuous 17-β-estradiol:
Continuous transdermal 17-β-estradiol 25 µg/24 hr, combined with continuous oral
micronized progesterone 100mg daily once daily in the evening.
• Group 3. Standard-dose continuous 17-β-estradiol:
Continuous transdermal 17-β-estradiol 50 µg/24 hr, combined with continuous oral
micronized progesterone 100mg daily once daily in the evening.
Study burden and risks
Baseline: Participants* medical history and family history will be collected.
The participants* height, weight and blood pressure will be measured, and a
chronotype and sleep quality questionnaire (MCTQ and PSQI) will be filled in at
baseline.
For screening purposes, blood samples will be collected (3 tubes) to assess
complete blood count, calcium, creatinine, ALAT, alkaline phosphatase, serum
FSH, TSH, HbA1c(%) and 25-hydroxyvitamin D (25(OH)D.
In addition, baseline measurements of P1NP, CTX, estradiol, fasting glucose,
and fasting insulin will be conducted (4 tubes), an oral glucose tolerance test
(OGTT) will be performed and an ultrasound of the liver will be performed
(fibroscan).
During treatment: P1NP, CTX, and serum estradiol will be measured every other
week from baseline until week 16 (one tube at each time point).
A fasting glucose, fasting insulin, and an oral glucose tolerance test (OGTT)
and an ultrasound of the liver will be performed (fibroscan) after 16 weeks of
treatment.
A chronotype questionnaire and sleep quality questionnaire and menopausal
symptoms questionnaire will be filled in at baseline and after 16 weeks of
treatment.
Benefits: Participation in the trial does not involve an expected individual
benefit for the participant other than relieving possible climacteric symptoms.
However, there might be a group benefit if physiological low-dose estrogen
therapy leads to increased bone turnover and improved treatment for the
prevention of osteoporosis in postmenopausal women.
Risks: Blood draws may cause bruising at the site of the punctured vein.
Participants may experience side effects of the transdermal 17-β-estradiol
treatment. The most common side effects are rash at the site of the transdermal
patch (20.8%), redness at the site of the patch (8.5%), itchiness at the site
of the patch (19.8%), headache (7.8%), and breast tenderness (6.6%) (SmPC
systen). Progesterone may cause the following side effects: vaginal bleeding,
breast tenderness, nausea, dizziness, somnolence (1-4 hours after
administration), headache (SmPC uterogestan). There is no excess risk of
venous thromboembolism in transdermal 17-β-estradiol users. Hormone replacement
therapy for less than 1 year does not lead to increased risk of breast cancer
(SmPC Systen).
Risks fat biopsy: Participants will experience discomfort during the
application of local anaesthesia, but thereafter the procedure is painless. A
subcutaneous hematoma will develop after the fat biopsy, but this will
gradually resolve. The subcutaneous fat biopsy can possibly cause bleeding or
an infection around the site of the biopsy.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
- Postmenopausal, defined as final menstrual cycle more than 12 months prior to
inclusion and FSH>30 IU/L
- Final menstrual cycle < 10 years prior to inclusion
- Age 45-60 years
Exclusion criteria
• Contra-indication for estrogen and/or progesterone therapy: Presence or
suspicion or history of breast cancer, endometrial cancer, ovarian cancer,
presence or history of venous thromboembolism, arterial thrombosis (e.g.
myocardial infarction, angina pectoris) inherited or acquired thrombophilia,
presence of liver disease, untreated endometrial hyperplasia, abnormal vaginal
bleeding, porphyria, uncontrolled or severe hypertension)
• First-grade family member with inherited thrombophilia or history of VTE
under the age of 60 years
• Hysterectomy
• Premature menopause (menopause age <40 years)
• Known hypersensitivity to the excipients in the estradiol patch: acrylate
copolymer, polyethylene terephthalate, α-tocopherol, soy allergy or peanut
allergy (component of progesterone capsule)
• Hormonal contraception or hormone replacement therapy use (estradiol with or
without progesterone) in the past 12 months
• Presence or history of any clinically relevant metabolic, endocrinological,
hepatic, renal, cardiovascular, gastrointestinal, or respiratory conditions,
history of bone disease or bone marrow disease, known vitamin D deficiency
(25-OH vitamin D <30 nmol/L)
• Recent fracture (<12 months)
• BMI <20 or BMI >=30
• Use of drugs including herbal medicine known to affect bone metabolism (e.g.
corticosteroids) or to interfere with cytochrome P450 enzyme (CYP) pathways.
Exceptions are occasional use of paracetamol, ibuprofen, acetylsalicylic acid
or topical medication
• For adipose tissue biopsy: anticoagulant treatment, allergy to lidocaine
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2022-003866-19-NL |
| CCMO | NL83336.018.23 |